1. Field of the Invention
The present invention relates to a method for producing optically active 3-hydroxyhexanoic acids useful as intermediates for synthesizing medicine and agricultural chemicals.
2. Description of the Prior Art
Lately, it has become important to synthesize physiologically active substances as optically active compounds. In a physiologically active substance having several kinds of optical isomers, these isomers often show a difference in activity. Among these isomers, one isomer has strong activity and the other isomers show weak activity or undesired toxicity. Accordingly, when the physiologically active substances are synthesized, it is desired to selectively synthesize preferable optical isomers not only to develop full physiological activity but also in safety.
Hitherto, as methods for obtaining optically active 3-hydroxyhexanoic acids, (i) a method for increasing carbons stereoselectively of an enolate derived from optically active acylthiazolidinethione or acyloxazolidinethione by an aldol reaction, and cleaving the enolate by methanolysis (Hsiao et al., J. Org. Chem., 52, 2201 (1987)), (ii) a method for ring-opening an optically active epoxide derived from an optically active .alpha.-amino acid (Mori et al., Tetrahedron, 45, 1639 (1989)), (iii) a method of cyclization of an optically active hemiamidal in the presence of a mercury catalyst, separation of a resultant diasteleomer mixture, and hydrolysis of the compounds (Cardillo et al., J. Chem. Soc. Perkin Trans. 1, 1487 (1990)), (iv) a method of optical resolution of racemic 3-hydroxyhexanes by a hydrolysis or ester synthesizing reaction in the presence of lipase originating from Candida cylindracea (Engel et al., Enzyme Microb, Technol., 13, 655 (1991)), (v) a method for asymmetrically oxidizing a substrate such an hexanoic acid, 2-hexenoic acid and hexanol in the presence of Candida rugosa (Hasegawa et al., EP 0089039A2), (vi) a method for asymmetrically reducing a .beta.-ketoester in the presence of Geotrichum candidum (Buisson et al., Biocatalysis, 5, 249 (1 992) and the like have been reported.
However, in method (i), since the amino acid leading an asymmetrical reaction as a starting material is used, it is relatively easy to obtain the S-compound of a natural type and it is difficult to obtain the R-compound of the antipode. Accordingly, in this method, only one of the optical isomers, the S-compound is sufficiently obtained. In method (ii), it is difficult to obtain the optically active .alpha.-amino acid of the starting material. Five troublesome steps are needed to obtain the product, and there are problems that the optical purity of the product is lowered (94% ee .fwdarw.76% ee) by racemization in the synthesis steps. In method (iii), there are problems of treatment of mercury which is used. It needs further unpractical column chromatography for separating diastereomer mixtures having low diastereo selectivity.
In method (iv), only products having low optical purity are obtained by either of hydrolysis and esterification. When racemic ethyl 3-acetoxyhexanoate is hydrolyzed into (S)-ethyl 3-hydroxyhexanoate, the resulting ester has low optical purity of 20% ee. In the reaction of racemic ethyl 3-hydroxyhexanoate and octanoic acid in an organic solvent, the reaction is troublesome due to esterification of the hydroxy group and acidolysis of the ethyl ester, and ethyl (S)-3-octanoyloxyhexanoate of the main product has unpreferable low optical purity (14% ee) . In methods (v) and (vi), since the substrate concentration is low, i.e., 1% or less, it is necessary to use reaction and treatment equipment in large scale for mass production. The 3-hydroxyhexanoic acids obtained by these methods are only R-compounds and not S-compounds.
As described above, these conventional methods have unsatisfactory problems of industrial level operation;